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Stapled Peptides Inhibitors: a New Window for Target Drug Discovery CORE Metadata, citation and similar papers at core.ac.uk Provided by University of Groningen University of Groningen Stapled Peptides Inhibitors Ali, Ameena M; Atmaj, Jack; Van Oosterwijk, Niels; Groves, Matthew R; Dömling, Alexander Published in: Computational and Structural Biotechnology Journal DOI: 10.1016/j.csbj.2019.01.012 IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below. Document Version Publisher's PDF, also known as Version of record Publication date: 2019 Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Ali, A. M., Atmaj, J., Van Oosterwijk, N., Groves, M. R., & Dömling, A. (2019). Stapled Peptides Inhibitors: A New Window for Target Drug Discovery. Computational and Structural Biotechnology Journal, 17, 263-281. https://doi.org/10.1016/j.csbj.2019.01.012 Copyright Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons). Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. Download date: 13-11-2019 Computational and Structural Biotechnology Journal 17 (2019) 263–281 Contents lists available at ScienceDirect journal homepage: www.elsevier.com/locate/csbj Mini Review Stapled Peptides Inhibitors: A New Window for Target Drug Discovery Ameena M. Ali, Jack Atmaj, Niels Van Oosterwijk, Matthew R. Groves, Alexander Dömling ⁎ Department of Drug Design, University of Groningen, Antonius Deusinglaan1, 9700AD Groningen, the Netherlands article info abstract Article history: Protein-protein interaction (PPI) is a hot topic in clinical research as protein networking has a major impact in Received 22 November 2018 human disease. Such PPIs are potential drugs targets, leading to the need to inhibit/block specific PPIs. While Received in revised form 28 January 2019 small molecule inhibitors have had some success and reached clinical trials, they have generally failed to address Accepted 29 January 2019 the flat and large nature of PPI surfaces. As a result, larger biologics were developed for PPI surfaces and they have Available online 19 February 2019 successfully targeted PPIs located outside the cell. However, biologics have low bioavailability and cannot reach α Keywords: intracellular targets. A novel class -hydrocarbon-stapled -helical peptides that are synthetic mini-proteins fi Stapled peptide locked into their bioactive structure through site-speci c introduction of a chemical linker- has shown promise. PPI Stapled peptides show an ability to inhibit intracellular PPIs that previously have been intractable with traditional Drug discovery small molecule or biologics, suggesting that they offer a novel therapeutic modality. In this review, we highlight Inhibitor what stapling adds to natural-mimicking peptides, describe the revolution of synthetic chemistry techniques and Synthetic chemistry how current drug discovery approaches have been adapted to stabilize active peptide conformations, including ring-closing metathesis (RCM), lactamisation, cycloadditions and reversible reactions. We provide an overview on the available stapled peptide high-resolution structures in the protein data bank, with four selected structures discussed in details due to remarkable interactions of their staple with the target surface. We believe that stapled peptides are promising drug candidates and open the doors for peptide therapeutics to reach currently “undruggable” space. © 2019 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Contents 1. Introduction.............................................................. 263 2. WhyStapledPeptides?......................................................... 264 3. ChemicalSynthesisofStapledPeptides.................................................. 265 3.1. Ring-ClosingMetathesis(RCM).................................................. 267 3.2. Lactamisation.......................................................... 268 3.3. Cycloadditions.......................................................... 269 3.4. ReversibleReactions....................................................... 269 3.5. ThioetherFormation....................................................... 269 4. StructuralInsightofStapledPeptidesTargetProtein-ProteinInteraction(PPI)inthePDB........................... 270 4.1. SAH-p53-8:Stapledp53PeptideBindsPotentlytoHumanMDM2.................................. 270 4.2. MDM2DoubleMacrocyclizationStapledPeptide:FastSelectionofCell-ActiveInhibitor......................... 270 4.3. SpecificMCL-1StapledPeptideInhibitorasApoptosisSensitizerinCancerCells............................ 272 4.4. Stapled Peptides SP1, SP2 Inhibit Estrogen Receptor ERβ ....................................... 272 5. ComputationalApproachforStaplePeptideDesign............................................. 275 6. Conclusion............................................................... 276 Acknowledgment.............................................................. 278 References................................................................. 279 ⁎ Corresponding author. E-mail address: [email protected] (A. Dömling). https://doi.org/10.1016/j.csbj.2019.01.012 2001-0370/© 2019 Published by Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). 264 A.M. Ali et al. / Computational and Structural Biotechnology Journal 17 (2019) 263–281 1. Introduction chemistry behind peptide stapling and provide an overview on some se- lected successful examples of peptide-based drugs to underline their Drug discovery approaches targeting protein-protein interactions importance. Lastly, we will underline four exclusive stapled-peptides (PPIs) has been fast-tracked over the present decade to deliver success- targeting PPIs, in which their staple makes an intimate interaction ful new drug leads and opens an expansive range of new therapeutic with the target interface, in order to reveal the role of stapling on pep- targets that were previously considered “undruggable”. This accelera- tide binding and their inhibition of PPIs. tion in PPI-based drugs is due to improved screening and design technologies, shortening the time between drug discovery to drug reg- 2. Why Stapled Peptides? istration and changing pharmaceutical economic delivery [1]. More- over, most human diseases are underpinned by a complex network of Helical peptides are one of the two main secondary structural ele- PPIs, (for example hubs such as p53), which underscores the need to ments in PPI interfaces, (in addition to β-sheets) and play a central understand PPIs not only on a clinical level, but also on molecular role in protein function within the cell. Often these elements are not sta- level. In this respect, the “omics” such as, genomics, RNA, proteomics ble in conformation in the absence of a complete protein fold. Addition- and metabolomics can accumulate huge volumes of data aiming at ally, peptides are sensitive to proteolysis by peptidases reducing their targeted and personalized medicine [2,3]. half-life (down to minutes), impacting their ability to penetrate cell All of the data, in addition to structural and screening-based membranes – all of which makes native peptides poor drug candidates approaches, have significantly expanded our understanding on PPI in- [14–16]. Notwithstanding, one main feature that makes peptides good terfaces that were previously highly challenging and difficult to target, drug candidates is their ability to bind large and relatively flat target sur- as these interacting surfaces are shallow or flat, non-hydrophobic and faces efficiently and specifically, which is a requirement in the majority large (1500-3000 Å). In addition, PPI surfaces differ in their shape and of intracellular therapeutically relevant PPIs. This makes peptides as an amino acid residue composition, particularly the hot spots that are es- attractive target for drug development and enables their transition into sential during binding protein partners; making small-molecules enti- the clinic [5,17]. The use of therapeutic peptides has grown explosively ties unlikely as protein therapeutics [4–8]. Moreover, the discovery of over the last three decades, covering areas such as metabolic diseases, innovative and drug lead molecules with the expected biological oncology, and cardiovascular diseases [ 18]. From a dataset that was col- activity and pharmacokinetics is the main aim of medicinal chemistry. lected recently on March 2018 and based on previously released data- Therefore, the application of ‘follow-on’-based strategy has always base report by Peptide Therapeutics Foundation, of 484 therapeutic been one of the most effective approaches that lead to promising bioac- peptides, 60 have
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